Wei-Zhao Peng1, Jin Zhao1, Xin Liu1, Chao-Feng Li1, Shuang Si1, Ren Ma2. 1. Department of General Surgery, China-Japan Friendship Hospital, Beijing, 100029, China. 2. Department of General Surgery, China-Japan Friendship Hospital, Beijing, 100029, China. maren517@sohu.com.
Abstract
BACKGROUND: Systematic profiling studies have implicated regulators of pre-mRNA splicing as important disease determinants in gastric cancer (GC), but the underlying mechanisms have remained elusive. Here we focused on hnRNPA2B1 splicing factor-dependent mechanisms governing GC development. METHODS: The expression of hnRNPA2B1 was analyzed among the Cancer Genome Atlas (TCGA) datasets of GC and validated at mRNA level. The function of hnRNPA2B1 in GC cells was analyzed and its downstream gene was identified using RNA immunoprecipitation. Further, effect of hnRNPA2B1 on BIRC5 alternative splicing was investigated. RESULTS: We show that overexpression of hnRNPA2B1 in GC is correlated with poor survival, and hnRNPA2B1 is required for maintaining GC malignant phenotype by promoting cell proliferation, inhibiting cell apoptosis and increasing cell metastasis. Mechanistically, hnRNPA2B1 co-expressed with several core spliceosome components and controls alternative splicing of anti-apoptotic factor BIRC5. BIRC5 isoform 202 (BIRC5-202) played the oncogenic function in GC cells, and overexpression of the BIRC5-202 transcript partly rescued the decrease in cisplatin resistance induced by downregulation of hnRNPA2B1. CONCLUSIONS: We demonstrate that hnRNPA2B1 regulates BIRC5 splicing and might act as a therapeutic target of chemo-resistant GC cells.
BACKGROUND: Systematic profiling studies have implicated regulators of pre-mRNA splicing as important disease determinants in gastric cancer (GC), but the underlying mechanisms have remained elusive. Here we focused on hnRNPA2B1 splicing factor-dependent mechanisms governing GC development. METHODS: The expression of hnRNPA2B1 was analyzed among the Cancer Genome Atlas (TCGA) datasets of GC and validated at mRNA level. The function of hnRNPA2B1 in GC cells was analyzed and its downstream gene was identified using RNA immunoprecipitation. Further, effect of hnRNPA2B1 on BIRC5 alternative splicing was investigated. RESULTS: We show that overexpression of hnRNPA2B1 in GC is correlated with poor survival, and hnRNPA2B1 is required for maintaining GC malignant phenotype by promoting cell proliferation, inhibiting cell apoptosis and increasing cell metastasis. Mechanistically, hnRNPA2B1 co-expressed with several core spliceosome components and controls alternative splicing of anti-apoptotic factor BIRC5. BIRC5 isoform 202 (BIRC5-202) played the oncogenic function in GC cells, and overexpression of the BIRC5-202 transcript partly rescued the decrease in cisplatin resistance induced by downregulation of hnRNPA2B1. CONCLUSIONS: We demonstrate that hnRNPA2B1 regulates BIRC5 splicing and might act as a therapeutic target of chemo-resistant GC cells.
Authors: Carles Barceló; Julia Etchin; Marc R Mansour; Takaomi Sanda; Mireia M Ginesta; Victor J Sanchez-Arévalo Lobo; Francisco X Real; Gabriel Capellà; Josep M Estanyol; Montserrat Jaumot; A Thomas Look; Neus Agell Journal: Gastroenterology Date: 2014-07-03 Impact factor: 22.682